11Beta-hydroxysteroid dehydrogenase 1 (hereinafter, “11beta-HSD1” or “HSD1”) catalyzes the interconversion of glucocorticoids (hereinafter, “GC”) between inert 11-keto forms (e.g. cortisone, 11-dehydrocorticosterone) and active 11beta-hydroxy forms (e.g. cortisol, corticosterone, respectively). The enzyme, in vivo, prefers the reductase direction from the 11-keto to the 11beta-hydroxy, in other words, the production of active GC.
11Beta-HSD1 is ubiquitously expressed, most notably in liver, lung, adipose tissue, vasculature, ovary and the central nervous system.
Until recently, experimental results have suggested that the active form of GC produced through HSD1 as well as the enzyme itself is involved in several biological actions and diseases.
For example, the active GC is known to stimulate gluconeogenic enzymes and have effects at least in part in inducing hyperglycemia. In this situation, HSD1 can be a second source of GC production in addition to the adrenal glands.
As another example, continuous excessiveness of the active GC in peripheral tissues, as observed in Cushing's syndrome, leads to insulin resistance, where HSD1 is considered to have an important role.
Also, in adipose tissue, active GC is demonstrated to enhance the differentiation of preadipocytes into adipocytes. Mature adipocytes express HSD1 activity, which causes an increase in local concentration of the active form and further expansion of adipose tissue. Such an action of HSD1 should be critical in pathogenesis of obesity.
In addition, a local immunosuppressive effect of HSD1 in placental deciduas, and a relationship between the expression of the enzyme in adrenal cortex and the induction of adrenaline synthesis, are suggested.
(The above are referred to in: Quinkler M, Oelkers W & Diederich S (2001) European Journal of Endocrinology Vol. 144, Pages 87-97; and Seckl J R & Walker B R (2001) Endocrinology Vol. 142, Pages 1371-1376.)
According to the above suggestions, it is expected that drugs having inhibitory effects against HSD1 would be useful for treating or preventing diabetes mellitus, obesity, metabolic syndrome in connection with any of such diseases, or any other diseases which occur by reason of the actions of HSD1.
Diabetes mellitus, main feature of which disease is chronic hyperglycemia, introduces various metabolic abnormalities and shows symptoms of thirst, polydipsia, polyuria, and so on based on high glucose concentration. Continuing hyperglycemic state would also lead to diabetic complications such as retinopathy, nephropathy, neuropathy, and myocardial and/or cerebral infarction by reason of arteriosclerosis.
In treating diabetes, moderate suppression of hyperglycemia is critical in order that onset and progress of the complications would be repressed. For these purposes, dietetics, ergotherapy and pharmacotherapy are utilized in combination on a suitable basis and, amongst the pharmacotherapy, many approaches different in mechanisms of action have been attempted. In spite of those various existing methods, sufficient therapeutic effect has not ever been achieved.
Obesity is defined as a state of fatness coinciding with any disease that would be improved or not be progressed in case of weight decrease (e.g. diabetes, hyperlipidemia, hypertension) or with an excessive amount of fat in viscera. It is considered that, if such a state should continue, at least two of diabetes, hyperlipidemia, hypertension and etc. would concur, and then onset of myocardial and/or cerebral infarction by reason of arteriosclerosis would occur.
Major therapeutic methods in treating obesity are dietetics and ergotherapy, and pharmacotherapy is undertaken only if necessary, for example, because of difficulty in the first two alternatives. However, the existing drugs have several problems in adverse effects and usages, since most of them suppress feeding mainly via central action.
In consequence, development of any drug to treat diabetes and/or obesity with a novel mechanism of action has so far been required. Under these circumstances, it is expected that drugs having inhibitory effects against HSD1 would be useful as another alternative with separate mechanistic approach to treat diabetes mellitus, as well as a novel “adipose tissue-acting” class among other drugs against obesity.
As drugs in development to treat diabetes and/or obesity through inhibition of HSD1, for example, WO 03/065983 discloses triazole compounds of the following general formula:
[wherein:    R1 is unsubstituted or substituted adamantyl;    W is —N(Ra)— or single bond;    X is —CH2— or single bond;    Z is —S— or single bond;    Ra is —H or C1-6 alkyl unsubstituted or substituted with one to five fluorines;    R2 is —H, unsubstituted or substituted C1-10 alkyl, unsubstituted or substituted C2-10 alkenyl, —CH2CO2H, —CH2CO2C1-6 alkyl, —CH2CONHRa, —(CH2)0-2C3-9 cycloalkyl (optionally having double bonds, and either unsubstituted or substituted), —(CH2)0-2C5-12 bicycloalkyl (optionally having double bonds, and either unsubstituted or substituted), —(CH2)0-2 adamantyl (either unsubstituted or substituted) or —(CH2)0-2R;    R3 is —H, unsubstituted or substituted C1-10 alkyl, unsubstituted or substituted C2-10 alkenyl, —YC3-9 cycloalkyl (optionally having double bonds, and either unsubstituted or substituted), —YC5-12 bicycloalkyl (optionally having double bonds, and either unsubstituted or substituted), —Yadamantyl (either unsubstituted or substituted) or YR;    R is benzodioxolane, furan, tetrahydrofuran, thiophene, tetrahydrothiophene, dihydropyran, tetrahydropyran, pyridine, piperidine, benzofuran, dihydrobenzofuran, benzothiophene, dihydrobenzothiophene, indole, dihydroindole, indene, indane, 1,3-dioxolane, 1,3-dioxane, phenyl or naphthyl (any such R unsubstituted or substituted); and    Y is —(CH2)0-2— or (—HC═CH—)].
However, any description under said application does not disclose nor refer to any of the compounds having the structure of the present invention.
The compounds of the present invention improve physicochemical (stability, etc.) and biological (activity to inhibit HSD1, specificity, bioavailability, metabolism, etc.) profiles, as a result of the selection of structural characteristics as disclosed herein.